US20060258655A1 - Crystalline forms of linezolid intermediate - Google Patents

Crystalline forms of linezolid intermediate Download PDF

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US20060258655A1
US20060258655A1 US11362312 US36231206A US2006258655A1 US 20060258655 A1 US20060258655 A1 US 20060258655A1 US 11362312 US11362312 US 11362312 US 36231206 A US36231206 A US 36231206A US 2006258655 A1 US2006258655 A1 US 2006258655A1
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oxazolidinyl
morpholinyl
oxo
fluorophenyl
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Tamas Koltai
Tamar Nidam
Viviana Braude
Serguei Fine
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Teva Pharmaceuticals USA Inc
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18Oxygen atoms
    • C07D263/20Oxygen atoms attached in position 2
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

The present invention relates to novel crystalline forms of the linezolid intermediate S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine referred to herein as Form A, Form B, and Form C.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application claims the benefit of provisional application Ser. Nos. 60/656,778, filed Feb. 24, 2005, 60/656,646, filed Feb. 24, 2005, and 60/690,822, filed Jun. 14, 2005, which are incorporated herein by reference.
  • FIELD OF THE INVENTION
  • The present invention relates to the solid state chemistry of the linezolid intermediate S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine.
  • BACKGROUND OF THE INVENTION
  • Linezolid [(S)—N-[[3-(3-Fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide] is an antimicrobial agent. Linezolid is an oxazolidinone, having the empirical formula C16H20FN3O4 and the following structure (I):
    Figure US20060258655A1-20061116-C00001
  • Linezolid is described in The Merck Index (13th edition, Monograph number: 05526, CAS Registry Number: 165800-03-3) as white crystals, with a melting point of 181.5-182.5°. Linezolid, as well as a process for its preparation, is disclosed in U.S. Pat. No. 5,688,792 (Example 5), European Patent No. 717738, Israeli Patent No. 110,802, Canadian Patent No. 2,168,560, and International Patent Publication WO 95/07271.
  • Crystalline Form III linezolid is disclosed in U.S. Pat. No. 6,559,305.
  • Linezolid is marketed in the United States by Pfizer, Inc. as an injection, tablets, and oral suspension under the name ZYVOX®. Its main indications are nosocomial pneumonia, skin and skin-structure infections, and vancomycin-resistant Enterococcus faecium infections.
  • U.S. Pat. No. 5,688,792 claims linezolid and its use for the treatment of microbial infections. This patent also discloses, but does not claim, the following method of preparation:
    Figure US20060258655A1-20061116-C00002
  • This method of preparation was also disclosed in Bricker, et al., J. Med. Chem., 39 673-679 (1996), where it was stated that the above route avoids the use of phosgene to make the carbamate precursor of the oxazolidinone ring. The authors also disclose that the use of NaN3 can be avoided by using potassium phthalimide, followed by deblocking of the phthalimide with aqueous methyl amine.
  • In the above-described synthesis, the intermediate amine, S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II)
    Figure US20060258655A1-20061116-C00003

    is reacted without isolation with acetic anhydride as an oily product, or in solution, to produce the acetamide, linezolid (I). This is followed by procedures for isolating the linezolid such as those described in U.S. Pat. No. 5,688,792, at col. 15, 11. 22-28 (chromatography and separation of the desired fraction, followed by evaporation and trituration of the product to obtain pure linezolid).
  • In the above-described syntheses, the intermediate azide R—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III)
    Figure US20060258655A1-20061116-C00004

    is reduced to its corresponding amine, S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) in the solvent ethyl acetate by hydrogenation using hydrogen gas and a palladium/carbon catalyst. These reaction conditions lead to the production of an undesirable level of reaction by-products, and, following the acetylation of the intermediate amine (II) to linezolid (I), to undesirably high levels of bis-linezolid (IV).
    Figure US20060258655A1-20061116-C00005
  • The present invention relates to the solid state physical properties of an intermediate of linezolid, S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II). These properties can be influenced by controlling the conditions under which S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) is obtained in solid form. One important solid state property is its rate of dissolution in aqueous fluid or its behavior on compaction and its storage stability.
  • These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form may give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form may also give rise to distinct spectroscopic properties that may be detectable by powder X-ray crystallography, solid state 13C NMR spectrometry and infrared spectrometry.
  • SUMMARY OF THE INVENTION
  • The present invention is based on the finding that the linezolid intermediate S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) can be obtained in at least three different crystalline forms: Form A, Form B, and Form C.
  • In one embodiment, the present invention provides a crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) referred to herein as Form A, characterized by a powder X-ray diffraction (PXRD) pattern with peaks at 13.2±0.2, 14.8±0.2, 15.1±0.2, and 25.0±0.2 degrees 2 theta or substantially as indicated in FIG. 1.
  • In one embodiment, the present invention provides a crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) referred to herein as Form B, characterized by a powder X-ray diffraction (PXRD) pattern with peaks at 15.6±0.2, 19.2±0.2, 22.5±0.2, and 24.3±0.2 degrees 2 theta or substantially as indicated in FIG. 2.
  • In one embodiment, the present invention provides a crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) referred to herein as Form C, characterized by a powder X-ray diffraction (PXRD) pattern with peaks at 5.8±0.2, 11.5±0.2, 19.6±0.2, and 26.3±0.2 degrees 2 theta or substantially as indicated in FIG. 3.
  • These new crystalline forms were found to be chemically pure (by HPLC) and found to be a single crystalline form (by PXRD). Each form contains less than about 5% of other crystalline forms of intermediate amine (II) and contains less than about 5% of the intermediate azide (III).
  • FIGURES
  • FIG. 1 shows the powder X-ray diffractogram of linezolid intermediate amine (II) Form A.
  • FIG. 2 shows the powder X-ray diffractogram of linezolid intermediate amine (II) Form B.
  • FIG. 3 shows the powder X-ray diffractogram of linezolid intermediate amine (II) Form C.
  • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention is based on the finding that the linezolid intermediate S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) can be obtained in at least three different crystalline forms: Form A, Form B, and Form C. Thus, the present invention provides novel solid crystalline forms of S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II), referred to herein as Form A, Form B, and Form C.
  • The crystalline Forms A, B, and C may be distinguished by their respective powder X-ray diffraction (PXRD) patterns. The crystalline forms have characteristic PXRD peak positions in the range of 2-40 degrees two theta. Crystalline Forms A, B, and C can be identified by these characteristic peak positions and the identity and quantify of their crystalline impurities can also be determined.
  • In one embodiment, the present invention provides a crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) referred to herein as Form A, characterized by a powder X-ray diffraction (PXRD) pattern with peaks at 13.2±0.2, 14.8±0.2, 15.1±0.2, and 25.0±0.2 degrees 2 theta. Form A maybe further characterized by PXRD peaks at 3.05 +0.2, 16.1±0.2, 17.9±0.2, 19.3±0.2, and 23.0±0.2 degrees 2 theta, substantially as depicted in FIG. 1.
  • In one embodiment, the present invention provides a crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) referred to herein as Form B, characterized by a powder X-ray diffraction (PXRD) pattern with peaks at 15.6±0.2, 19.2±0.2, 22.5±0.2, and 24.3±0.2 degrees 2 theta. Form B may be further characterized by PXRD peaks at 7.2±0.2, 14.6±0.2, 16.5±0.2, 20.1±0.2, and 23.0±0.2 degrees 2 theta, substantially as depicted in FIG. 2.
  • In one embodiment, the present invention provides a crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) referred to herein as Form C, characterized by a powder X-ray diffraction (PXRD) pattern with peaks at 5.8±0.2, 11.5±0.2, 19.6±0.2, and 26.3±0.2 degrees 2 theta. Form C may be further characterized by PXRD peaks at 13.2±0.2, 20.4±0.2, 21.6±0.2, 22.3±0.2, 23.0±0.2, and 23.8±0.2 degrees 2 theta, substantially as depicted in FIG. 3.
  • The characteristic PXRD peaks of the novel crystalline forms of the intermediate amine (II) are shown in Table 1, with the most characteristic peaks indicated in bold.
    TABLE 1
    Characteristic PXRD peaks in degrees 2 theta
    Form A Form B Form C
    3.0 7.2 5.8
    13.2 14.6 11.5
    14.8 15.6 13.2
    15.1 16.5 19.6
    16.1 19.2 20.4
    17.9 20.1 21.6
    19.3 22.5 22.3
    23.0 23.0 23.0
    25.0 24.3 23.8
    26.3
  • The crystalline Forms A, B, and C of S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) of the present invention may be substantially pure with respect to other crystalline forms, i.e., the novel forms contain less than about 10%, preferably less than about 5%, and even more preferably less than about 1% (by weight) of other crystalline forms of S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II). In certain embodiments, the novel crystalline forms contain less than about 10%, preferably less than about 5%, and even more preferably less than about 1% (by weight) of amorphous S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II).
  • The present invention is not intended to encompass true solutions of S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) wherein the crystal structure of the novel crystalline Forms A, B, and C and the properties that distinguish the novel crystalline forms of the present invention are lost. Thus, the preferred form of the present invention is that of solid forms of crystalline Forms A, B, and C. However, the use of the novel forms to prepare solutions (e.g., so as to provide a material for conversion into linezolid (I)) is considered to be within the contemplation of the invention.
  • Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
  • HPLC Method
  • Column Hypersil Gold 150×4.6, 5μ
  • Detection limit: 0.1%
  • Eluents: K2HPO4 0.01M: MeOH A: 80:20 B: 50:50
    TABLE 2
    Time A B Flow
    0 100 0 1.5
    15 57 43 2
    25 35 65 2

    Powder X-Ray Diffraction
  • Powder X-ray diffraction data were obtained by methods known in the art using a SCINTAG® powder X-ray diffractometer model X'TRA® equipped with a solid state detector. Copper radiation of 1.5418 Å was used. A round aluminum sample holder with round zero background quartz plate was used, with cavity of 25(diameter)* 0.5(depth) mm. The obtained characteristic peaks were in the range of 2-40 degrees two theta.
  • EXAMPLES Example 1 Preparation of Intermediate Amine (II) Crystalline Form B
  • In a 1L reactor, 6 g R—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) was charged with 150 ml ethyl acetate, followed by 0.6 g 10% Pd/C. The system was flushed 3 times with nitrogen and 3 times with hydrogen. The pressure of hydrogen was set to 1.5 atm. The reaction mixture was stirred at RT and the reaction followed by TLC or HPLC until completion. The reaction mixture was filtered through celite and the solution was evaporated to obtain 4.6 g S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) as a white solid. The crystals were analyzed by PXRD and showed a novel form of) the intermediate amine (II) (Form B, 91.7% total purity by HPLC).
  • Example 2 Preparation of Intermediate Amine (II) Crystalline Form C
  • In a 10L reactor, 150 g R—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) was charged, followed by 15 g Pd/C in 5L toluene. Finally 500 ml ammonium hydroxide was added. The system was flushed 3 times with nitrogen and 3 times with hydrogen. The pressure of hydrogen was set to 1.5 atm. The reaction mixture was stirred at RT and the reaction followed by TLC or HPLC until completion. The reaction mixture was filtered through celite. S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) precipitated on standing and/or cooling as a white solid, was filtered, and dried at 50° C. overnight. The crystals obtained were analyzed by PXRD and showed a novel form of the intermediate amine (II) (Form C, 98.6% total purity by HPLC).
  • Example 3 Preparation of Intermediate Amine (II) Crystalline Form A
  • In a three necked flask, 6.4 g R—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) was charged, followed by 2.5 g ammonium formate, 23 ml ethanol, and 2.6 g zinc powder. The reaction mixture was stirred at RT and the reaction followed by TLC or HPLC until completion. 60 ml acetone were then added. The reaction mixture was filtered and by evaporation S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) was obtained as a solid. The crystals obtained were analyzed by PXRD and showed a novel form of the intermediate amine (II) (Form A, 96.5% total purity by HPLC).

Claims (12)

  1. 1. A crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) characterized by a powder X-ray diffraction (PXRD) pattern with peaks at 13.2±0.2, 14.8±0.2, 15.1±0.2, and 25.0±0.2 degrees 2 theta.
  2. 2. The crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) of claim 1 further characterized by PXRD peaks at 3.0±0.2, 16.1±0.2, 17.9±0.2, 19.3±0.2, and 23.0±0.2 degrees 2 theta.
  3. 3. The crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) of claim 1 which contains less than 5% by weight of other crystalline forms of S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II).
  4. 4. The crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) of claim 1, characterized by a powder X-ray diffraction (PXRD) pattern substantially as indicated in FIG. 1.
  5. 5. A crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II), characterized by a powder X-ray diffraction (PXRD) pattern with peaks at 15.6±0.2, 19.2±0.2, 22.5±0.2, and 24.3±0.2 degrees 2 theta.
  6. 6. The crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) of claim 5 further characterized by PXRD peaks at 7.2±0.2, 14.6±0.2, 16.5±0.2, 20.1±0.2, and 23.0±0.2 degrees 2 theta.
  7. 7. The crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) of claim 5 which contains less than 5% by weight of other crystalline forms of S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II).
  8. 8. The crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) of claim 5, characterized by a powder X-ray diffraction (PXRD) pattern substantially as indicated in FIG. 2.
  9. 9. A crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II), characterized by a powder X-ray diffraction (PXRD) pattern with peaks at 5.8±0.2, 11.5±0.2, 19.6±0.2, and 26.3±0.2 degrees 2 theta.
  10. 10. The crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) of claim 9 further characterized by PXRD peaks at 13.2±0.2, 20.4±0.2, 21.6±0.2, 22.3±0.2, 23.0±0.2, and 23.8±0.2 degrees 2 theta.
  11. 11. The crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) of claim 9 which contains less than 5% by weight of other crystalline forms of S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II).
  12. 12. The crystalline S—N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine (II) of claim 9, characterized by a powder X-ray diffraction (PXRD) pattern substantially as indicated in FIG. 3.
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WO2012019862A1 (en) 2010-08-11 2012-02-16 Synthon B.V. Process for making linezolid
EP2690100A1 (en) 2010-08-11 2014-01-29 Synhton B.V. Process for making linezolid
WO2014071990A1 (en) 2012-11-09 2014-05-15 Synthon Bv Process for making linezolid

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WO2011114210A3 (en) 2010-03-15 2011-12-01 Jubilant Life Sciences Limited Processes for the preparation of linezolid
WO2011137222A1 (en) 2010-04-30 2011-11-03 Indiana University Research And Technology Corporation Processes for preparing linezolid
WO2012094622A3 (en) * 2011-01-07 2012-10-18 The Regents Of The University Of California Amination of aryl alcohol derivatives
EP2852580A1 (en) 2012-01-24 2015-04-01 Jubilant Life Sciences Ltd. Improved process for the preparation of stable crystalline form-i of linezolid, substantially free of residual solvent
EP2989097A4 (en) * 2013-04-25 2017-11-08 Symed Labs Limited Improved processes for the preparation of linezolid using novel intermediates

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